The present invention relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives, to a process for their preparation, their use for the preparation of pharmaceutical compositions and pharmaceutical compositions containing these compounds.
The treatment of chronic and non-chronic painful conditions is extremely important in medicine. There is a worldwide need for effective treatment of pain for patient-oriented and target-oriented treatment of chronic and non-chronic painful conditions, this concept being interpreted as the successful and satisfactory treatment of pain for the patient. This is manifested by the large number of scientific studies which have appeared recently in the field of applied analgesics and basic research in nociception.
Conventional opioids such as morphine are very effective in the therapy of strong to very strong pain. However, their use is limited by the known side effects, for example respiratory depression, vomiting, sedation, constipation and tolerance development. Furthermore, they are less effective for neuropathic or incidental pain suffered inter alia by tumor patients.
Opioids deploy their analgesic effect by binding to membrane receptors belonging to the family known as G-protein-coupled receptors (GPRC). The biochemical and pharmacological characterization of subtypes of these receptors has now raised hopes that subtype-specific opioids have a different profile of effects and side effects from, for example morphine. Further pharmacological investigations have in the meantime made the discovery of a plurality of subtypes of these opioid receptors (xcexc1, xcexc2, xcexa1, xcexa2, xcexa3, xcex41 and xcex42) possible. There are further receptors and ion channels which participate substantially in the pain development and pain transmission system. The NMDA (N-methyl-D-as partate) ion channel is particularly important: a substantial proportion of synaptic communication takes place through it. The exchange of calcium ions between the neuronal cell and its environment is controlled by this channel.
Information about the physiological significance of ion channel-selective substances has been obtained through the development of patch clamp technology. The effect of NMDA antagonists on the influx of calcium ions into the interior of the cell can thus be clearly demonstrated. It has also been found that these substances have an independent antinociceptive potential (for example, ketamine). It is important here that the mechanism of action is quite different, for example, from opiates, as NMDA antagonists intervene directly in the crucial calcium balance of the cells during the transmission of pain. It has therefore been possible, for the first time, to treat the neuropathic forms of pain successfully.
Various NMDA antagonists, which were tetrahydroquinoline derivatives in this case, have already been described in J. Med. Chem. (1992) 35, 1954-1968, J. Med. Chem. (1992) 35, 1942-1953 and Med. Chem. Res. (1991) 1; 64-73 and patent applications EP 386 839, WO 97/12879 A1, WO 98/07704 A1 and WO 98/42673 A1. A large number of possible indications, including the treatment of pain, have been mentioned, in particular, in the patent applications. However, the effectiveness and usefulness of these substances are still uncertain, so there is a need for further substances here.
One object of the invention was to provide analgesically acting substances, in particular NMDA antagonists, suitable for treating pain, in particular also chronic and neuropathic pain. In addition, these substances should have the fewest possible side effects such as nausea, vomiting, dependency, respiratory depression or constipation.
The invention accordingly relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of general formula I, in the form of their racemates, enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, 
wherein
either
R1 and R2 together, respectively singly or multiply substituted or unsubstituted, form
xe2x80x94(CH2)nxe2x80x94 with n=3-10,
xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, 
R3 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by N, S or O, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R4 is selected from
R4a or ZR4a wherein Z is respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkinyl, and R4a is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
C(O)R9, C(O)OR9, C(S)R9, C(S)OR9 or SO2)R9 with R9 selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-,3- or 4-pyridyl; thiazolyl;
SR10 with R10 selected from
respectively singly or multiply substituted or unsubstituted aryl or heteroaryl,
C(O)NR11R12, C(O)NR11NR12R13, C(NR11)NR12R13, C(S)NR11R12 or C(S)NR11NR12R13, wherein R11, R12 and R13, independently of one another, are selected from
H; respectively branched or unbranched, singly or multiply substituted or un-substituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R5, R6, R7 and R8, independently of one another, are selected from
H, F, Cl, Br, I, CN, NO2; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl;
OR14, OC(O)R14, OC(S)R14, C(O)R14, C(O)OR14, C(S)R14, C(S)OR14, SR14, S(O)R14 or S(O2)R14, wherein R14 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
NR15R16, NR15C(O)R16, C(NR15)NR16R17, NR15C(S)R16, C(S)NR15R16 or C(S)NR15NR16R17 or S(O2)NR15R16, wherein R15, R16 and R17, independently of one another, are selected from
H, O; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
or
R15 and R16 or R16 and R17 together form a saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; or
R5 and R6, R6 and R7, or R7 and R8 jointly form
xe2x95x90CR18xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90 or xe2x95x90CHxe2x80x94CR18xe2x95x90CHxe2x80x94CHxe2x95x90,
xe2x80x83wherein R18 is
H, F, Cl, Br, I, OH or respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl;
xe2x80x83providing that
if R1 and R2 together form xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94
xe2x80x83and R3 corresponds to (xe2x88x92)p-menthan-3-ol, in particular menthol or borneol, R7=Cl and R5, R6 and R8=H do not simultaneously apply,
if R1 and R2 together form xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and R3 corresponds to CH3, R7=H, Cl or OCH3 and R5, R6 and R8=H do not simultaneously apply,
if R1b and R2a together form xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and R3 corresponds to H,
R7=OCH3 or C(O)NH2 and R5, R6 and R8=H, R5 and R7=CH3 and R6 and R8=H or R5=OCH3 and R6, R7 and R8=H do not simultaneously apply,
and
if R1b and R2a together form 
xe2x80x83or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 and R3 corresponds to C2H5, R7=H, Cl, CH3, OCH3 or NO2 and R5, R6 and R8=H or R5=NO2 and R6, R7 and R8=H do not simultaneously apply;
or
R1 is selected from
branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; singly or multiply substituted or unsubstituted alkyl aryl; singly or multiply substituted or unsubstituted aryl;
OR19, SR19, SO2R19 with R19 being selected from
respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstituted alkyl aryl, aryl, alkyl heteroaryl or heteroaryl;
R2 is selected from
H; branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl; singly or multiply substituted or unsubstituted phenyl; wherein, if R2 is phenyl, R1 has to be aryl, O-aryl or S-aryl,
R3 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by N, S or O, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R4 is selected from
R4a or ZR4a wherein Z is respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C6 alkyl; C2-C6 alkenyl or C2-C6 alkinyl, wherein R4a is
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
C(O)R9, C(O)OR9, C(S)R9, C(S)OR9 or S(O2)R9 with R9 being selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-,3- or 4-pyridyl; thiazolyl;
SR10 with R10 being
respectively singly or multiply substituted or unsubstituted aryl or heteroaryl,
C(O)NR11R12, C(O)NR11NR12R13, C(NR11)NR12R13, C(S)NR11R12 or C(S)NR11NR12R13, wherein R11, R12 and R13, independently of one another, are selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R5, R6, R7 and R8, independently of one another, are
H, F, Cl, Br, I, CN, NO2; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl;
OR14, OC(O)R14, OC(S)R14, C(O)R14, C(O)OR14, C(S)R14, C(S)OR14, SR14, S(O)R14 or S(O2)R14, wherein R14 is
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
NR15R16, NR15C(O)R16, C(NR15)NR16R17, NR15C(S)R16, C(S)NR15R16 or C(S)NR15NR16R17 or S(O2)NR15R16, wherein R15, R16 and R17, independently of one another, are
H, O; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
or
R15 and R16 or R16 and R17 together form a saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; or
R5 and R6, R6 and R7 or R7 and R8 jointly form
xe2x95x90CR18xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90 or xe2x95x90CHxe2x80x94CR18xe2x95x90CHxe2x80x94CHxe2x95x90, with R18 selected from
H, F, Cl, Br, I, OH or respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl;
providing that
if R4, R6, R7 and R8=H,
R1=CH3, R3=H or CH3 and R2 and R5=H do not simultaneously apply;
R1 is unsubstituted phenyl, R3=C2H5 and R2 and R5=H do not simultaneously apply;
if R4, R6, R7 and R8=H,
R1=S-phenyl, R2=H, R7=Cl and R3=CH3 do not simultaneously apply; or
R1=xe2x80x94S-2-pyridinyl, R2=CH3, R7=OCH3 and R3=xe2x80x94CH3xe2x80x94CHxe2x95x90CH2 do not simultaneously apply; or
if R2, R4, R5 and R7=H and R6 and R8=Cl,
R1=dioxalan and R3=xe2x80x94CH2xe2x80x94CH2xe2x80x94OH do not simultaneously apply.
The 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention are NMDA antagonists which act selectively on the glycine binding site and also exhibit pronounced analgesic response.
In the context of this invention, the term substituted as used in connection with alkyl, alkenyl, alkinyl and cycloalkyl or the xe2x80x9ccorresponding heterocyclexe2x80x9d refers to the substitution of a hydrogen radical by F, Cl, Br, I, NH2, SH or OH, multiply substituted radicals being radicals which are multiply substituted at different or at identical atoms, or both, for example triply at the same carbon atom as in the case of CF3 or at different sites as in the case of xe2x80x94CH(OH)xe2x80x94CHxe2x95x90CHxe2x80x94CHCl2.
xe2x80x94C(O)xe2x80x94 represents 
and this also applies to xe2x80x94C(S)xe2x80x94 or xe2x80x94S(O)xe2x80x94 and xe2x80x94S(O2)xe2x80x94.
The term xe2x80x9cC1-C8 alkylxe2x80x9d and xe2x80x9cC1-C10 alkylxe2x80x9d in the context of this invention refers to hydrocarbons containing 1 to 8 and 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, n-butane, sec-butyl, tert-butyl, n-pentane, neopentyl, n-hexane, n-heptane, n-octane, n-nonane and n-decane.
The term xe2x80x9cC1-C18 alkylxe2x80x9d in the context of this invention refers to hydrocarbons containing 1 to 18 carbon atoms. Examples include unsubstituted or singly or multiply substituted methyl, ethyl, propyl, isopropyl, n-butane, sec-butyl, tert-butyl, n-pentane, neopentyl, n-butane, sec-butyl, tert-butyl, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-dodecane, n-tridecane, n-tetradecane, n-pentadecane, n-hexadecane, n-heptadecane and n-octadecane.
The term xe2x80x9cC2-C10 alkenylxe2x80x9d and xe2x80x9cC2-C10 alkinylxe2x80x9d or xe2x80x9cC2-C18 alkenylxe2x80x9d and xe2x80x9cC2-C18 alkinylxe2x80x9d in the context of this invention refers to hydrocarbons containing 2 to 8 and 2 to 18 carbon atoms. Examples include unsubstituted or singly or multiply substituted methenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and unsubstituted or singly or multiply substituted methinyl, propinyl, butinyl, pentinyl, hexinyl, heptinyl, and octinyl.
The term xe2x80x9cC3-C7 cycloalkylxe2x80x9d in the context of this invention refers to cyclic hydrocarbons containing 3 to 7 carbon atoms. Examples include saturated or unsaturated, unsubstituted or singly or multiply substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term xe2x80x9ccorresponding heterocyclexe2x80x9d in the context of the invention refers to a C3-C7 cycloalkyl in which at least one carbon atom in the ring is replaced by S, O or N. Examples include pyrrolidine, pyrane, thiolane, piperidine and tetrahydrofuran.
The term xe2x80x9carylxe2x80x9d in the context of this invention refers to phenyls, naphthyls or anthracenyls. The aryl radicals may also be condensed with further rings.
The term xe2x80x9cheteroarylxe2x80x9d in the context of this invention refers to aromatic compounds which are optionally provided with a partially condensed ring system and contain at least one heteroatom from the group comprising nitrogen, oxygen and/or sulphur. Examples from this group include thiophen, furan, pyrrol, pyridine, pyrimidine, quinoline, isoquinoline, phtlalazine or quinazoline.
The term xe2x80x9calkylarylxe2x80x9d and xe2x80x9calkylheteroarylxe2x80x9d in the context of this invention refers to aryls and heteroaryls substituted at least with C1-C6 alkylene, the terms aryl, heteroaryl and alkyl having the same meaning as above, in which the bond is produced via the alkyl radical.
With respect to xe2x80x9carylxe2x80x9d, xe2x80x9calkylarylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d or xe2x80x9calkylheteroarylxe2x80x9d in the context of this invention, the term singly or multiply substituted refers to the substitution of the ring system with F, Cl, Br, I, NH2, SH, OH, CF3; xe2x95x90O or xe2x95x90S; singly or multiply substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C2-C8 alkenyl, C2-C8 alkinyl; phenyl or benzyl or dioxolyl; at one or more atoms.
The term concerning the salt formed with a physiologically acceptable acid in the context of this invention refers to salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals. Hydrochloride is particularly preferred.
The application particularly preferably relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I in which R4 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl;
C(O)R9 with R9 being
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, respectively singly or multiply substituted or unsubstituted aryl or heteroaryl, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-,3- or 4-pyridyl; or thiazolyl.
Particularly preferred are substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R4 is selected from
H; unsubstituted or singly or multiply substituted C1-C10 alkyl; unsubstituted or singly or multiply substituted phenyl; preferably H, CH3 or C2H5, in particular H.
The application preferably relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R3 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by N or O; singly or multiply substituted or unsubstitued alkyl aryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl.
Particularly preferred are substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R3 is selected from
H; branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl; singly or multiply substituted or unsubstituted phenyl, benzyl or phenethyl, preferably H, CH3 or C2H5, in particular H.
Particularly preferred are substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R1 and R2 together form
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, (xe2x80x94CH2xe2x80x94)n with n=3-6, preferably 3 or 6, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, 
xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94, in particular xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94.
The application also preferably relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R1 is selected from unsubstituted or singly or multiply substituted phenyl, naphthyl or anthracenyl; OR19 or SR19 with R19 being
branched or unbranched, singly or multiply substituted or unsubstituted C1-C6 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl; singly or multiply substituted or unsubstituted aryl;
preferably anthracenyl, naphthyl or, in particular, phenyl, unsubstituted or singly or multiply substituted with a substituent selected from:
F, Cl, Br, I, methoxy, ethoxy, propoxy, methyl, ethyl, propyl (n-propyl, i-propyl), butyl (n-butyl, i-butyl, t-butyl), carboxy, nitro, benzyloxy, phenyl, hydroxy, phenoxy, tri-fluormethyl, dioxolyl or SCH3 
or OR19 or SR19 with R19 being
branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl; or singly or multiply substituted or unsubstituted aryl;
in particular unsubstituted phenyl, naththyl and anthracenyl; O-hydroxyethyl, ethoxynaphthyl, 4-hydroxy-3-methoxyphenyl, 4-propoxyphenyl, 2,3,4-trimethulphenyl, 2,4,5-trimethoxyphenyl, SCH3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-dichlorophenyl, 4-carboxyphenyl, 3-nitrophenyl, 2,4,6-trimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-biphenyl, 4-methylphenyl, 4-ethoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 4-hydroxy-3-methoxyphenyl, 4-methylhydroxyphenyl, 4-hydroxyphenyl, 4-phenoxyphenyl, 4-nitrophenyl, 4-chloromethylphenyl, 4-tert-butylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-acetoxyphenyl, 4-cyanophenyl, 2-methoxyphenyl, 2,6-difluorophenyl, 2-trifluoromethylphenyl, 3-trifuloromethylphenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 2-, 3- or 4-benzyloxyphenyl, or S-phenyl or 6-chlorobenzo[1,3]dioxol-5-yl.
The application also preferably relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to Formula 1, in which R2 is selected from
H; branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl; singly or multiply substituted or unsubstituted phenyl, preferably H, unsubstituted phenyl; 4-methoxyphenyl or CH3, in particular H.
The application preferably relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R5, R6, R7 and R8, independently of one another, are selected from
H, F, Cl, Br, I, CN, NO2; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl;
OR14, C(O)R14, C(O)OR14 or SR14, wherein R14 is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C3-C8 cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
NR15R16, NR15C(O)R16, wherein R15 and R16, independently of one another, are selected from
H, O; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkinyl.
Particularly preferred are substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which R5, R6, R7 and R8, independently of one another, are selected from
H, F, Cl, Br, I, CN, NO2; respectively branched or unbranched, singly or multiply substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkinyl;
OR14, C(O)R14, C(O)OR14 or SR14, wherein R14 is selected from
H; branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl; singly or multiply substituted or unsubstituted aryl,
preferably R5, R6, R7 and R8, independently of one another, are selected from
H, F, Cl, Br, I, CN; branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl;
OR14 or SR14, with R14 selected from
branched or unbranched, singly or multiply substituted or unsubstituted C1-C4 alkyl; singly or multiply substituted or unsubstituted aryl,
in particular R5, R6, R7 and R8, independently of one another, are selected from the group consisting of
H, F, Cl, Br, I, CN; CH3, CF3, t-butyl, i-butyl, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94SCH3, and xe2x80x94O-phenyl.
Quite particularly preferred are substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention of Formula I, in which
R5, R6 and R8 represent H and R represents Cl or
R5 and R7 represent H and R6 and R8 represent Cl.
The application preferably relates, in particular, to the following substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention:
7,9-dichloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
7,9-dichloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid,
8-chloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
8-chloro-3a-4,5,9b-tetrahydro-3H-cyclo-penta[c]quinoline-4-carboxylic acid,
6-chloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
2-phenoxy-5,6a,11,11a-tetrahydro-6H-indene[1,2-c]quinoline-6-carboxylic acid ethyl ester,
6-chloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-7-trifluoromethyl-4-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2-hydroxy-ethoxy)-6-trifluoromethoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-naphthalene-2-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,7,8,12b-hexahydrobenzo[k]phenanthridine-6-carboxylic acid ethyl ester,
6-iodo-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-o-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ester,
5,7-dichloro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-p-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-p-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2,5-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-(4-tert-butylphenyl)-5,7-dichloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3,4-bis(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3,4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3-methyl-4-(2,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-o-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
7,9-dichloro-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
1,3-dichloro-7,10-methano-5,6,6a,7,8,9,10,10a-octahydrophenanthridine-6-carboxylic acid ethyl ester,
5,6a,7,11b-tetrahydro-6H-indeno-[2,1-c]quinoline-6-carboxylic acid ethyl ester,
10,12-dichloro-6b,7,8,12b-tetrahydro-8-azabenzo[j]fluoroanthrene-7-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,11a-tetrahydro-11-oxa-5-aza-benzo[a]fluoroene-6-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,11a-tetrahydro-11-thia-5-aza-benzo[a]fluoroene-6-carboxylic acid ethyl ester,
7,8-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-cyano-4-(2,3,4-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6,8,9-trichloro-2,3,3a,4,5,9b-hexahydro-furo[3,2-c]quinoline-4-carboxylic acid,
8-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,6,8-trichloro-4-(4-hydroxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(3,4-dimethoxyphenyl)-8-iodo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-iodo-4-(4-methylsulphanylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-ethoxy-3-methoxyphenyl)-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2-ethoxy-naphthalene-1-yl)-6-iodo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-4-(4-propoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2,4-dimethoxy-3-methylphenyl)-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
2-trifluoromethoxy-5,6,6a,7,8,9,10,11,12,12a-decahydro-5-aza-cycloocta-[a]naphthalene-6-carboxylic acid ethyl ester,
6-sec-butyl-4-(6-chlorobenzo[1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-anthracene-9-yl-6-chloro-8-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-sec-butyl-4-naphthalene-1-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-hydroxyphenyl)-3-methyl-8-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-4-naphthalene-2-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-methoxyphenyl)-3-methyl-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-chloro-8-fluoro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-bromophenyl)-6-chloro-8-fluoro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
7,8-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-chloro-4-(4-chlorophenyl)-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
2-cyano-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinoline-6-carboxylic acid ethyl ester,
4-(2-chlorophenyl)-6-cyano-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-bromo-8-chloro-3-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-bromo-8-chloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-bromo-4-(2-bromophenyl)-8-chloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-hydroxy-3-methoxyphenyl)-3-methyl-6-methylsulphanyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-cyano-3,4-bis-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-3,4-bis-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-(4-benzyloxy-3-methoxyphenyl)-6-tert-butyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
1,3-dichloro-5,6,6a,7,8,12b-hexahydrobenzo[k]phenanthridine-6-carboxylic acid,
1,3-dichloro-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinoline-6-carboxylic acid, and
5,7-dichloro-4-(3,5-dimethyl-phenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid.
Substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention in the form of their hydrochloride salts are particularly preferred.
The invention also relates to a process for preparing substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention.
Various processes for preparing tetrahydroquinolines are described in the literature:
a solid phase formulation (WO 98/34111),
multi-stage process control (WO 98/42673; Bioorganic and Medicinal Chemistry Letters Vol. 2, p. 371,1992; Journal of Heterocyclic Chemistry Vol. 25, p. 1831, 1988; Journal of the Chemical Society, Perkin Transactions 1 (1989), page 2245) or
a Lewis acid-catalysed xe2x80x9cOne-packxe2x80x9d process (Journal of the Chemical Society, Chemical Communications, 1999, p. 651; Journal of the American Chemical Society, Vol. 118, p. 8977, 1996).
However, all these processes obviously have a few drawbacks.
The present invention uses a xe2x80x9cone-packxe2x80x9d process as the basic process. The inventive process uses trifluoroacetic acid, in which a respective aromatic amine, aldehyde and electron-rich olefin component react with one another.
Substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I, wherein R4=H, whereas the other radicals have one of the aforementioned meanings are initially prepared by the basic process. Anilines according to Formula II, in which R5, R6, R7 and R8 have one of the meanings already given 
are reacted with a glyoxalic acid ester according to Formula III and olefins according to Formula IV, in which R1 and R2 have one of the meanings already given, with trifluoroacetic acid at between 0 and 100xc2x0 C. It is preferred if the reaction period lasts 0.25 to 12 hours, preferably a maximum of 2 h. The reaction preferably takes place at a temperature between 20 and 40xc2x0 C., preferably at ambient temperature and/or the reaction is a one-pack reaction.
A decisive advantage of the process according to the invention is that the process leads very selectively to the desired compounds in high yields through a domino reaction (imine formation and subsequent aza-Diels-Alder reaction).
Without the need to carry out a linking or cleavage stage, as with the solid phase formulation, and also without purification of the intermediate stages, as with the described solution chemistry, the process according to the invention is distinguished by its ease of implementation and also by its method of purification. Products of high purity can for the most part be obtained by repeated washing with non-polar solvents, for example n-hexane. Otherwise, they may be purified by column chromatography. In particular, pure diastereomer compounds of Formula I may be obtained by washing with non-polar solvents, for example n-hexane, or by crystallization of their salts, for example the hydrochlorides.
Most reagents used here, in particular of Formulae I, III and IV, are commercially available or may be prepared by synthesis methods well-known to a person ordinarily skilled in the art.
After the basic process, the products formed during the basic process may be reacted in subsequent reactions by procedures well-known to a person ordinarily skilled in the art to form secondary products of Formula I, the hydrogen initially being substituted at R4.
Thus, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=alkyl, formyl, acyl, sulphenyl and sulphonyl, the reaction product after completion of the basic reaction may be reacted with corresponding chloro- or fluoroformiates, acid chlorides, sulphenyl chlorides and sulphonyl chlorides in the presence of a base, preferably triethyl amine, pyridine or NaOH in water, dioxan and water mixtures or THF and water mixtures at a temperature between 0 and 20xc2x0 C. (J. Org. Chem. 1989, 54, 5574-5580).
Similarly, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=CSNR17, the reaction product after completion of the basic reaction may be reacted with a thionation reagent, preferably Lawesson""s reagent (2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,2,3,4-dithiaphosphetane), in organic solvents, preferably THF or toluene at a temperature of 30 to 50xc2x0 C.
Or, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=C(O)N13R14 or C(S)N13N14, the reactionproduct after completion of the basic reaction may be reacted with potassium cyanate or potassium isothiocyanate in water at temperatures of up to 100xc2x0 C. or with organic isocyanates or isothiocyanates in alcohols, preferably methanol, ethanol or isopropanol at temperatures up to boiling point.
Furthermore, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=C(NR13)NR14R15, the reaction product after completion of the basic reaction may be reacted under alkaline conditions with O-methylisoureas or S-methylisothio ureas at temperatures of 20 to 50xc2x0 C., preferably ethanolic or methanolic NaOH or KOH.
Furthermore, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=C(O)NR13R14, the reaction product after completion of the basic reaction may be reacted in water/glacial acetic acid at 30 to 60xc2x0 C. with propanone-2-semicarbazone.
Similarly, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=C(S)NR13R14, the reaction product after completion of the basic reaction may be reacted in water/NaOH at 30 to 60xc2x0 C. with CS2 and hydrazines.
As the last possibility to be mentioned here, if the product is to be substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R4=alkyl, benzyl or phenethyl, the reaction product on completion of the basic reaction may be reacted with a corresponding alkylation halide, benzyl halide or phenethyl halide and a suitable base, preferably sodium hydride or potassium tert-butylate, in a solvent, for example ethanol, at between 0 and 100xc2x0 C. (J. Org. Chem. 1947, 12, 760; Zh. Obshch. Khim 1942, 12, 418).
It may also be desirable to use starting products of Formula III in which R3xe2x89xa0H and R3 are preferably alkyl, in particular CH3 and C2H5 for the basic process for preparing substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of Formula I wherein R3=H. After the basic process and also the subsequent reactions possibly following it, the reaction product is saponified with a corresponding base, preferably with 6N NaOH in ethanol at temperatures between 0 and 100xc2x0 C. (Organikum, 1990, p. 418).
Under many of the aforementioned reaction conditions, OH, SH and NH2 groups may possibly enter undesirable secondary reactions. It is therefore preferable to provide them with protective groups or to replace NH2 with NO2 and to eliminate the protective group prior to purification of the end product or to reduce the NO2 group. The invention therefore also relates to a variation of the above-described process in which, in the starting compounds, at least one OH group has been replaced by a OSi(Ph)2tert-butyl group, at least one SH group has been replaced by a S-p-methoxybenzyl group and/or at least one NH2 group has been replaced by a NO2 group and, prior to purification of the end product, at least one, preferably all, OSi(Ph)2tert-butyl group(s) is eliminated with tetrabutyl ammonium fluoride in tetrahydrofuran and/or at least one, preferably all, p-methoxybenzyl group(s) is eliminated with a metal amine, preferably sodium amine and/or at least one, preferably all, NO2 group(s) reduced to NH2.
Furthermore, carboxylic acid or thiocarboxylic acid groups are sometimes unstable under the aforementioned reaction conditions, so it is preferable to use their methyl esters in the reactions and then to saponify the reaction product with KOH solution or NaOH solution in methanol at 40 to 60xc2x0 C. The invention therefore also relates to a variation of the above-described process in which prior to purification of the end product, a product of the process with at least one C(O)OCH3 and/or C(S)OCH3 group is saponified with KOH solution or NaOH solution in methanol at 40 to 60xc2x0 C.
The substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention are toxicologically safe, so they are suitable as pharmaceutical active ingredient in pharmaceutical compositions.
The invention therefore also relates to a pharmaceutical composition containing, as active ingredient, at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to the invention of Formula I, also in the form of their racemates, enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt.
Preferred pharmaceutical compositions are those which contain, as active ingredient, at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to Formula I, wherein
R5, R6 and R8 represent H and R7 represents Cl, or
R5 and R7 represent H and R6 and R8 represent Cl.
Particularly preferred pharmaceutical compositions are those which contain at least one of the following substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention:
7,9-dichloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
7,9-dichloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid,
8-chloro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
8-chloro-3a-4,5,9b-tetrahydro-3H-cyclo-penta[c]quinoline-4-carboxylic acid,
6-chloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
2-phenoxy-5,6a,11,11a-tetrahydro-6H-indene[1,2-c]quinoline-6-carboxylic acid ethyl ester,
6-chloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-7-trifluoromethyl-4-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2-hydroxy-ethoxy)-6-trifluoromethoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-naphthalene-2-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,7,8,12b-hexahydrobenzo[k]phenanthridine-6-carboxylic acid ethyl ester,
6-iodo-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-o-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ester,
5,7-dichloro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-p-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-p-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2,5-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-(4-tert-butylphenyl)-5,7-dichloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(2-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3,4-bis(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(3,4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-3-methyl-4-(2,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-o-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(3-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-bromophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-chloro-4-(2-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
7,9-dichloro-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-4-carboxylic acid ethyl ester,
1,3-dichloro-7,10-methano-5,6,6a,7,8,9,10,10a-octahydrophenanthridine-6-carboxylic acid ethyl ester,
5,6a,7,11b-tetrahydro-6H-indeno-[2,1-c]quinoline-6-carboxylic acid ethyl ester,
10,12-dichloro-6b,7,8,12b-tetrahydro-8-azabenzo[j]fluoroanthrene-7-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,11a-tetrahydro-11-oxa-5-aza-benzo[a]fluoroene-6-carboxylic acid ethyl ester,
1,3-dichloro-5,6,6a,11a-tetrahydro-11-thia-5-aza-benzo[a]fluoroene-6-carboxylic acid ethyl ester,
7,8-dichloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-cyano-4-(2,3,4-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6,8,9-trichloro-2,3,3a,4,5,9b-hexahydro-furo[3,2-c]quinoline-4-carboxylic acid,
8-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,6,8-trichloro-4-(4-hydroxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(3,4-dimethoxyphenyl)-8-iodo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-iodo-4-(4-methylsulphanylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-ethoxy-3-methoxyphenyl)-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2-ethoxy-naphthalene-1-yl)-6-iodo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-4-(4-propoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(2,4-dimethoxy-3-methylphenyl)-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
2-trifluoromethoxy-5,6,6a,7,8,9,10,11,12,12a-decahydro-5-aza-cycloocta-[a]naphthalene-6-carboxylic acid ethyl ester,
6-sec-butyl-4-(6-chlorobenzo[1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-anthracene-9-yl-6-chloro-8-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-sec-butyl-4-naphthalene-1-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-hydroxyphenyl)-3-methyl-8-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-4-naphthalene-2-yl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-methoxyphenyl)-3-methyl-6-phenoxy-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-chloro-8-fluoro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-4-m-tolyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-bromophenyl)-6-chloro-8-fluoro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
7,8-dichloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-chloro-4-(4-chlorophenyl)-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
2-cyano-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinoline-6-carboxylic acid ethyl ester,
4-(2-chlorophenyl)-6-cyano-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-bromo-8-chloro-3-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
6-bromo-8-chloro-4-(2,4-dimethylphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-bromo-4-(2-bromophenyl)-8-chloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
4-(4-hydroxy-3-methoxyphenyl)-3-methyl-6-methylsulphanyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
6-cyano-3,4-bis-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
8-chloro-6-fluoro-3,4-bis-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
4-(4-benzyloxy-3-methoxyphenyl)-6-tert-butyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
5,7-dichloro-4-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
1,3-dichloro-5,6,6a,7,8,12b-hexahydrobenzo[k]phenanthridine-6-carboxylic acid,
1,3-dichloro-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinoline-6-carboxylic acid, and
5,7-dichloro-4-(3,5-dimethyl-phenyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid
in the form of their racemates, enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt.
The pharmaceutical compositions according to the invention may be administered in liquid form in the form of injection solutions, droplets or juices, in semi-solid forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols and, in addition to at least one substituted tetrahydroquinoline derivative according to the invention, optionally contain, depending on the formulation, excipients, fillers, solvents, diluents, colorants and/or binders. The choice of auxiliary materials and the amounts to be used depend on whether the pharmaceutical composition is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to infections on the skin, the mucous membranes or the eyes. Preparations in the form of tablets, dragees, capsules, granules, droplets, juices and syrups are suitable for oral administration, solutions, suspensions, readily reconstitutable dry preparations as well as sprays for parenteral, topical and inhalative administration. Substituted tetrahydroquinoline derivatives according to the invention deposited in dissolved form or in a plaster, optionally with addition of agents which promote skin penetration, are preparations which are suitable for percutaneous administration. Orally or percutaneously administered preparations are able to release the substituted tetrahydroquinoline derivatives according to the invention after a delay. The amount of active ingredient to be administered to the patient varies according to the patient""s weight, the method of administration, the indication and the severity of the disease. It is normal to administer 2 to 500 mg/kg (active ingredient/body weight) of at least one substituted tetrahydroquinoline derivative according to the invention of Formula I.
Preferably, the substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention are used for the treatment of pain, in particular chronic and neuropathic pain, but also migraine, so the invention also relates to the use of at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to the invention of Formula I in the form of their racemates, enantiomers, or diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt, for preparing a pharmaceutical composition for the treatment of pain, in particular neuropathic and/or chronic pain and/or for the treatment of migraine.
The affinity at the NMDA receptor has lead to further fields of application as NMDA antagonists are known to have inter alia a neuroprotective activity and can therefore also readily be used for syndromes such as Parkinson""s disease and Huntington""s chorea, etc., accompanied by neurodegeneration and damage. Further indications for the NMDA antagonists according to the invention include epilepsy, glaucoma, osteoporosis, ototoxicity, withdrawal phenomena following alcohol and/or drug abuse, stroke and associated cerebral ischaemia, cerebral infarcts, cerebral oedema, hypoxia, anoxia and also to be used for anxiolysis and in anaesthesia. Therefore, the invention also relates to the use of at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to the invention of Formula I also in the form of their racemates; enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt, for preparing a pharmaceutical composition for the treatment/prophylaxis of/during epilepsy, Parkinson""s disease, Huntington""s chorea, glaucoma, ototoxicity, withdrawal symptoms following alcohol and/or drug abuse, stroke, cerebral ischaemia, cerebral infarcts, cerebral oedema, hypoxia, anoxia and/or anxiolysis and/or anaesthesia.
It has surprisingly been found that the substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention are also very suitable for further indications, in particular for the treatment of urinary incontinence, itching, tinnitus aurium and/or diarrhoea. Therefore, the instant invention also relates to the use of at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative of Formula I, also in the form of their racemates; enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt, for preparing a pharmaceutical composition for the treatment of urinary incontinence, itching, tinnitus aurium and/or diarrhoea.
However, the compounds according to the invention are also effective in other indications. Therefore, the invention also relates to the use of at least one substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative of Formula I, also in the form of their racemates; enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt, for preparing a pharmaceutical composition for the treatment/prophylaxis of/during schizophrenia, Alzheimer""s disease, psychoses caused by a raised amino acid level, AIDS dementia, encephalomyelitis, Gilles de La Tourette""s syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory tract diseases, coughs and/or mental illnesses.
The invention also relates to a method for treating a non-human mammal or a human requiring treatment of medically relevant symptoms by administration of a therapeutically effective dose of a substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to the invention of Formula 1, also in the form of its racemates; enantiomers, diastereomers, in particular mixtures of its enantiomers or diastereomers or of an individual enantiomer or diastereomer; its bases and/or salts of physiologically acceptable acids, in particular of the hydrochloride salt, or of a pharmaceutical composition according to the invention. The invention relates, in particular, to corresponding processes for the treatment of pain, in particular neuropathic and/or chronic pain and/or for the treatment of migraine, for the treatment of urinary incontinence, itching, tinnitus aurium and/or diarrhoea, for the treatment/prophylaxis of/during epilepsy, Parkinson""s disease, Huntington""s chorea, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms following alcohol and/or drug abuse, stroke, cerebral ischaemia, cerebral infarcts, cerebral oedema, hypoxia, anoxia and/or anxiolysis and/or anaesthesia or for the treatment/prophylaxis of/during schizophrenia, Alzheimer""s disease, psychoses caused by a raised amino acid level, AIDS dementia, encephalomyelitis, Gilles de La Tourette""s syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory tract diseases, coughs and/or mental illnesses.
The invention will be described hereafter by examples and figures, without being restricted thereto.